Saw palmetto extract (SPE) has seen wide use in Europe for self treatment of benign prostatic hyperplasia (BPH), although the mechanism of action on the human prostate is unknown and efficacy of treatment remains unproven. Suggested mechanisms include inhibition of androgen action and an anti-inflammatory effect. These possibilities were evaluated by study of prostate biopsy specimens obtained before and after treatment with SPE in men during a 6 month randomized clinical trial vs a placebo. Ultrasound-guided sextant biopsies were obtained from 41 men prior to and after 6 months of placebo (n=20) or SPE (n=20) treatment (320 mg/day). The 82 tissue samples were batch processed by routine histology; by morphometry for quantitative tissue composition of the inner and outer gland; by a histopathologic scoring system for acute and chronic inflammation and for atrophy; by immunohistochemical assessment of apoptosis, cell proliferation, and androgen receptor expression ; an d by a tissue homogenate assay for androgen levels (expressed as ng/g of prostate tissue). A contraction in the transition zone epithelium from 17.8% before to 10.7% after 6 months of treatment was found in the SPE group (p < 0.01). In a parallel, independent analysis, the epithelial atrophy scores increased from 25.2% before to 40.9% after SPE (p < 0.01). In placebo patients, no significant changes were seen in any tissue measures. None of the other tissue studies revealed any significant changes from baseline during SPE treatment. SPE appears to exert a suppressant effect on the prostatic epithelium, especially the transition zone. Since no alterations in prostatic androgen metabolism or apoptosis markers could be demonstrated, the data suggest that the effect is mediated by a mechanism unrelated to changes in tissue hormone concentrations, receptor expression or to obvious anti-inflammatory effects. How epithelial suppression related to clinical effects, in the absence of pro state volume contraction, is not clear. However, our observation of significant epithelial involution following 6 months of SPE use should encourage further investigation. FUNDING Urological Sciences Research Foundation PUBLICATIONS None PUBLICATIONS None